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CHICAGO -- While the widely reported adverse effects of long-term bisphosphonate treatment in osteoporosis patients are certainly real, undertreatment of fracture risk now appears to be gaining, a prominent rheumatologist warned in a lecture here.

A long-term trend toward declining rates of hip fracture has stopped in recent years, accompanied (if not actually triggered) by a marked fall in use of osteoporosis medications of all types in at-risk patients who have already suffered fractures, said Kenneth Saag, MD, MSc, of the University of Alabama at Birmingham.

Speaking at the American College of Rheumatology's 2018 State of the Art Symposium, Saag said that bisphosphonate "sabbaticals" may cut the risk of osteonecrosis and atypical fractures known to be associated with these agents -- but that substituting alternative drugs may be preferable to stopping all osteoporosis medications.

By now, the risks associated with bisphosphonates when continued for many years are well known to all physicians: femoral fractures and others considered atypical in the senior population, and osteonecrosis of the jaw. In both cases, the clinical manifestations can come suddenly and without warning.

This has led to many questions from patients and controversy within the medical community, Saag said. Patients who have been taking these agents for several years want to know whether they should stop, and physicians are still debating the maximum duration of treatment.

Saag noted that, at the outset of bisphosphonate therapy, steps can be taken to reduce some of the risks. For example, optimizing dental health before starting treatment can prevent osteonecrosis of the jaw, or at least the clinical problems stemming from it.

With respect to atypical fractures, Saag said a point to bear in mind is that the risk remains well below that for the osteoporotic fractures that bisphosphonate prevent. He cited 2011 data indicating that, for bisphosphonate therapy, the number needed to harm for atypical fracture was 417 over 3 years, whereas the number needed to treat for osteoporotic hip and vertebral fracture was 91 and 14, respectively.

That means that, "for every atypical stress fracture caused, at least 30 vertebral and five hip fractures are prevented," he said.

Nevertheless, the risk of adverse effects rises with duration of therapy whereas the preventive benefit does not. At some point, stopping bisphosphonates must be considered.

Monitoring via conventional radiographs, DXA scans, and/or advanced imaging is one way to determine that point for individual patients, Saag suggested.

He proposed bisphosphonate "sabbaticals," defined as an extended stoppage of therapy, as opposed to the more traditional "holiday" concept, for patients found to be at risk for adverse bisphosphonate effects and yet still at risk for osteoporotic fractures.

But that doesn't necessarily mean taking the patients off medications altogether, he stressed. A number of alternatives exist, although these come with their own downsides including adverse effects and costs.

One such alternative is so-called anabolic agents such as teriparatide (Forteo) and abaloparatide (Tymlos), peptide drugs that mimic parathyroid hormone. These have shown strong effects in promoting bone mineral density without risk of atypical fractures or jaw osteonecrosis.

Another possibility is denosumab (Prolia). Like bisphosphonates, it inhibits bone resorption (rather than promoting bone formation) and has been tied to osteonecrosis and atypical fractures, though at relatively low rates.

Both types of drug, though, are branded products and therefore costly. Also, stopping denosumab appears to cause rapid bone loss, approaching 10% of bone density in just a few months with consequent increases in fracture risk. This is less of an issue with bisphosphonates, which accumulate in bone and are actually re-released into the circulation at pharmacologically active levels (perhaps contributing to their adverse effects).

Saag briefly discussed a issued last year by the American College of Physicians. He noted that osteoporosis is very often managed in primary care, and the guideline does a "reasonable" job in giving direction for generalists. He credited the ACP guideline with highlighting the need for awareness of bisphosphonates' adverse effects and the concept of interrupting treatment.

At the same time, however, he criticized the ACP recommendations as overly simplistic. They come across as one-size-fits-all and thus aren't so helpful for treating "nuanced patients" seen in specialty clinics; fail to address the risks of treatment interruption; and give short shrift to anabolic agents in patients who need to come off bisphosphonates, he said.

But perhaps the biggest problem related to bisphosphonates has been the widespread publicity about their adverse effects. Trends through the early 2010s indicated sharp declines in use of oral bisphosphonates in the U.S. One dataset showed that prescriptions fell by half just from 2008 to 2012. Another indicated that use of any anti-osteoporosis medication among patients with an osteoporotic fracture history declined by nearly 50% from 2002 to 2012.

Many of the questions about long-term management of bisphosphonates might have been answered in a major trial Saag had hoped to mount, called Effectiveness of Discontinuing Bisphosphonates (EDGE). He said that yielded promising results, but then balked at the projected $20-million price tag for the full trial.

Currently, he said, the for specialists, published in 2015. But while it gave fairly specific guidance on when to initiate a bisphosphonate holiday, it had little to say about when to restart therapy.

So for that crucial question, Saag said, the answer is simply, "We don't know." It falls to individual clinicians to use their own judgment on the basis of bone turnover markers, radiographic evidence, and other factors in individual patients.

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